cooperative lewis acid ― onium salt catalysis as tool for ... · cooperative lewis acid ― onium...
TRANSCRIPT
Cooperative Lewis Acid―Onium Salt Catalysis as Tool for the Desymmetrization of meso-
Epoxides
Florian Broghammer,a Daniel Brodbeck,a Thorsten Junge,a and René Peters*a
a. Universität Stuttgart, Institut für Organische Chemie, Pfaffenwaldring 55, 70569 Stuttgart, Germany. E-mail: [email protected]
Electronic Supplementary Material (ESI) for ChemComm.This journal is © The Royal Society of Chemistry 2016
Table of contents
Experimental .................................................................................................................................4
General Procedures .......................................................................................................................5
General Procedure for the Synthesis of Ammonium and Pyridinium Salts (GP1) .........................5
General Procedure for the Formation of the C2-Symmetric Ligands (GP2) ...................................5
General Procedure for the Synthesis of the C1-Symmetric Ligands (GP3) ....................................5
General Procedure for the In-Situ-Formation of Catalysts (GP4) .................................................7
General Procedure for the Desymmetrization of Epoxides with Acetyl Bromide (GP5) ................7
Substrate Synthesis ........................................................................................................................8
cis-Stilbene Oxide (1a) ................................................................................................................8
cis-2,3-Bis(3-fluorophenyl)oxirane (1b).......................................................................................8
Ligand Synthesis........................................................................................................................... 10
Synthesis of the Onium Salts .................................................................................................... 10
Catalysis ....................................................................................................................................... 17
Isolation of Catalyst 3c ............................................................................................................. 17
In situ formation of catalyst 3d ................................................................................................. 18
(1S,2S)-2-Bromo-1,2-diphenylethyl acetate (4a) ....................................................................... 18
(1S,2S)-2-Bromo-1,2-di-p-tolylethyl acetate (4b) ...................................................................... 19
(1S,2S)-2-Bromo-1,2-di-m-tolylethyl acetate (4c) ...................................................................... 20
(1S,2S)-2-Bromo-1,2-bis(4-fluorophenyl)ethyl acetate (4d)....................................................... 20
(1S,2S)-2-Bromo-1,2-bis(3-fluorophenyl)ethyl acetate (4e) ....................................................... 21
(1S,2S)-2-Bromo-1,2-bis(4-(trifluoromethyl)phenyl)ethyl acetate (4f) ....................................... 22
(1S,2S)-2-Bromo-1,2-bis(3-(trifluoromethyl)phenyl)ethyl acetate (4g) ...................................... 23
(1S,2S)-2-Bromo-1,2-bis(3-chlorophenyl)ethyl acetate (4h) ...................................................... 23
(1S,2S)-2-Bromo-1,2-bis(3-methoxyphenyl)ethyl acetate (4i) ................................................... 24
Derivatization .............................................................................................................................. 25
(1S,2R)-2-Azido-1,2-diphenylethyl acetate (6) .......................................................................... 25
(1S,2R)-2-Azido-1,2-diphenylethylethan-1-ol (7) ....................................................................... 26
(1S,2R)-1,2-Diphenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl acetate (8) ................................... 26
Kinetic Comparison between catalysts 3d and 3e ......................................................................... 27
Spectral data ................................................................................................................................ 28
HPLC-Data ................................................................................................................................ 49
References ................................................................................................................................... 59
Experimental
All reactions were performed in oven-dried glassware (stored at 150 °C in an oven and afterwards
heated to 630 °C for 5 minutes under vacuum using a heat-gun) and unless otherwise indicated
under a positive pressure of nitrogen (0.2 bar). Liquids were added via syringe, solids were added
neat against a flow of nitrogen. Solvents were removed by the use of a rotary-evaporator with a
bath temperature of 40 °C and pressures between 10 and 700 mbar. Non-volatile compounds were
dried in vacuo at 0.1 mbar. For work-up procedures and flash chromatography, distilled technical
grade solvents were used. Dichloromethane (DCM), diethyl ether, tetrahydrofuran (THF), toluene
and acetonitrile used for reactions and purification of the catalysts/ligands were dried under
nitrogen using a solvent purification system. n-Hexane and i-propanol for HPLC were purchased in
HPLC-quality and used without further purification. Acetic acid was distilled over P2O5 and LiBr
was dried in a Kugelrohr-oven (0.1 mbar, 250 °C, overnight). The epoxides used in catalysis were
prepared according to literature procedures (see below). All other laboratory chemicals were
purchased from commercial suppliers and were used without purification unless otherwise
indicated. Yields refer to purified compounds and are calculated in mol% of the starting material
used. Expect as otherwise indicated, reactions were magnetically stirred and monitored by NMR-
spectroscopy or thin layer-chromatography (TLC) using silica gel plates (silica gel 60 F254).
Visualization occurred by fluorescence quenching under UV light and / or by staining with ceric
ammonium molybdate. Flash-chromatography was performed on silica-gel 60 (40-63 µm particle
size), using a moderate pressure applied via hand-pump or nitrogen-flow. In reactions and during
catalysis where low temperatures are necessary a cryostatic temperature regulator was used. NMR
spectra were recorded at room temperature on spectrometers operating at 700, 500, 400, 300 or
250 MHz (1H), 125 or 75 MHz (13C) and 376 MHz (19F). Chemical shifts δ are referred in terms of
ppm, coupling constants J are given in Hz. The following classify the multiplicity: s = singulet,
d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br = broad signal. Infrared spectra
were recorded by the IR-service of the Universität Stuttgart on a FT-IR spectrometer with ATR unit
and the signals are given by wavenumbers (cm-1). Optical rotation was measured on a polarimeter
operating at the sodium D line with a 100 mm path cell length. Melting points were measured using
a melting point apparatus in open glass capillaries and are uncorrected. Mass spectra were obtained
from the MS-service of the Universität Stuttgart and the methods used are stated below. The er
values were determined by HPLC using a chiral stationary phase (methods are shown below).
General Procedures
General Procedure for the Synthesis of Ammonium and Pyridinium Salts (GP1)
The aldehyde (1.0 equiv., 1.0 mmol) was dissolved in acetonitrile (1 mL of acetonitrile / 1.0 mmol
of aldehyde) and the amine/pyridine-derivative (1.1 equiv.) was added. The mixture was stirred for
15 h, after which diethyl ether was added to cause precipitation (10 mL / 1.0 mmol aldehyde). The
supernatant solvent was decanted and the precipitate was washed with diethyl ether three times and
dried in vacuo.
General Procedure for the Formation of the C2-Symmetric Ligands (GP2)
This synthesis followed a published protocol.[1] Molecular sieves (4Å 100 mg/mmol) and the
corresponding onium salt (2.0 equiv.) were added to a solution of (1R,2R)-()-diaminocyclohexane
(1.0 equiv.) in ethanol at ambient temperature and the mixture was stirred for 24 hours. After
filtration, ethanol was removed in vacuo. Subsequent repetitive azeotropic removal of residual
ethanol with DCM gave the corresponding pure ligand.
General Procedure for the Synthesis of the C1-Symmetric Ligands (GP3)
Mono-Protonation of the Diaminocyclohexane[2]
To a rapidly stirred solution of (1R,2R)-()-diaminocyclohexane (1.0 equiv.) in diethyl ether, HCl
(1.0 equiv., 4 M in dioxane) was slowly added and the resulting mixture was stirred for 15 h at
room temperature. The excessive solvent was removed in vacuo and the residue was washed three
times with diethyl ether (10 mL). The obtained white powder was used without further purification.
Diimine Formation
Similar to a literature protocol[2] the protonated diamine 9b (1.0 equiv.) was dissolved in MeOH
and molecular sieves (4Å) and aldehyde 10 (1.0 equiv. in MeOH) was added. The resulting mixture
was stirred for three hours. A solution of the second aldehyde (1.0 equiv.) in MeOH was slowly
given to the reaction and after 5 minutes NEt3 (1.0 equiv.) was added dropwise. The yellow
solution was stirred for additional 15 h. Afterwards the solvent was removed in vacuo and the
residue was dissolved in toluene. After filtration over celite, repetitive azeotropic removal of
residual toluene with DCM gave a yellow solid, which was washed with n-pentane till the washing
phase showed no more yellow color. After removing the last residues of solvent under reduced
pressure the ligands were obtained as bright yellow powders.
General Procedure for the In-Situ-Formation of Catalysts (GP4)
A Schlenk-flask was charged with the respective ligand (0.01 mmol), which was dissolved in DCM
(0.5 mL). After five minutes of stirring, a solution of the corresponding aluminum source
(1.0 equiv., 0.01 mmol, 1.0 M in heptane) was added dropwise and the resulting solution was
stirred for an additional three hours. The in situ formed catalysts were then directly used without
further purification.
General Procedure for the Desymmetrization of Epoxides with Acetyl Bromide (GP5)
N N
O OAlCl
O
R R
NBr 3d
5 mol% x,5 mol% AcOH,AcBr, DCM, -40 °C,48 h then 1 h RT
Br
R OAc
R
To a solution of the in situ generated catalyst 3d (0.05 equiv. 0.01 mmol) in DCM (0.50 mL) the
corresponding epoxide (1.00 equiv, 0.20 mmol), acetic acid (0.05 equiv., 0.01 mmol, 0.6 µL in
20.0 µL DCM as a stock solution) and acetyl bromide (10.00 equiv, 2.00 mmol, 245.9 mg,
149.0 µL) were successively added at 40 °C and the mixture was stirred for 48 h at this
temperature. Afterwards the flask was removed from the cooling bath and the reaction mixture
stirred for an additional hour at ambient temperature. The reaction was quenched by the addition of
Hünig’s base (0.2 mL) and the resulting mixture was diluted with DCM (2 mL) and filtered over a
short pad of silica gel. The solvent was removed and the residue was purified by column
chromatography (petrol ether/ethyl acetate 30:1) to obtain the desired products.
Substrate Synthesis
cis-Stilbene Oxide (1a)
Substrate x which was used throughout the reported investigation as the standard substrate was
prepared according to literature known procedures starting from diphenyl acetylene.[3,4]
cis-2,3-Bis(3-fluorophenyl)oxirane (1b)
Intermediate 1b1 was synthesized using a literature known protocol.-[5] A dry Schlenk flask was
charged with CuI (0.20 equiv., 1.0 mmol, 190.4 mg) and PdCl2(PPh3)2 (0.12 equiv., 0.6 mmol,
442.2 mg) under a nitrogen atmosphere. Dry benzene (50 mmol) was added followed by 1-fluoro-
3-iodobenzene (2.0 equiv., 10.0 mmol, 2.22 g, 1.16 mL), DBU (12.0 equiv., 60 mmol, 9.13 g,
8.96 mL) and trimethylsilylacetylene (1.0 equiv. 5.0 mmol, 491.1 mg, 0.71 mL). Water (0.8 equiv.,
4.0 mmol, 72.0 mg, 72 µL) was added and the flask was wrapped in aluminum foil to protect it
from light radiation. The reaction mixture was stirred at 60 °C for 24 h. Afterwards the reaction
was quenched by the addition of saturated aqueous NH4Cl solution (25 mL) and stirred for ten
minutes at ambient temperature. The phases were separated and the aqueous one extracted with
diethyl ether three times (50 mL). The combined organic phases were washed with brine (100 mL),
dried over Mg2SO4 and the solvent was removed under reduced pressure. Column chromatography
(petrol ether) of the residue yielded the desired product 1b1 (0.98 g, 92%) as a white solid.
C14H8F2, MW: 214.21 g/mol. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.36-7.28 (m, 4H, ArH),
7.25-7.22 (m, 1H, ArH), 7.22-7.20 (m, 1H, ArH), 7.10-7.03 (m, 2H, ArH).
Synthesis of the (Z)-olefin 1b2 followed a known procedure procedure.[6] The alkyne 1b1 (1 equiv.,
3.0 mmol, 0.64 g) was put into a dry Schlenk flask and dissolved in THF (20.0 mL). The mixture
was cooled to 78 °C and Ti(OiPr)4 (2 equiv., 6.0 mmol, 1.71 g, 1.78 mL) followed by n-BuLi (6
equiv., 12.0 mmol, 0.67 g, 7.5 mL 15% in hexane) were added. The dark red solution was stirred at
this temperature for 15 minutes and then heated to 50 °C. After 3 hours at this temperature the
reaction was quenched by the addition of saturated aqueous NH4Cl solution (10.0 mL) and stirred
for an additional 5 minutes. Afterwards the phases were separated and the aqueous one was
extracted three times with diethyl ether (25 mL). The combined organic phases were washed with
brine (50.0 mL), dried over MgSO4 and the solvent was removed under reduced pressure. Column
chromatography (petrol ether) of the residue yielded the desired olefin (0.52 g, 80%) a clear oil.
C14H10F2, MW: 216.23 g/mol. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.24-7.16 (m, 2H, ArH),
7.02-6.96 (m, 2H, ArH), 6.94-6.85 (m, 4H, ArH), 6.59 (s, 2H, CH=CH).
For the epoxidation of the olefin 1b2 a literature know procedure[7] was employed. A flask was
charged with olefin 1b2 (1.00 equiv., 1.22 mmol), which was solved in DCM (2.5 mL) and cooled
down to 0 °C. After stirring for 5 minutes at 0 °C MeReO3 (2.5 mol%, 0.03 mmol, 7.6 mg),
pyridine (0.15 equiv., 0.18 mmol, 14.5 mg, 14.8 µL) and H2O2 (1.50 equiv., 1.83 mmol, 207.5 mg,
0.21 mL 30% in water) were added consecutively. The mixture was allowed to warm up to ambient
temperature and rapidly stirred for 48 h. To quench the reaction MnO2 (2.0 mg) was added and the
mixture was diluted with DCM. After separation of the phases the aqueous one was extracted three
times with DCM (2.00 mL). The combined organic phases were dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was purified by column chromatography (petrol
ether/ ethyl acetate 30:1) to yield the desired epoxide 1b as a white solid (0.16 g, 57%).
C14H10F2O, MW: 232.07 g/mol. M.p.: 65 °C. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.20-7.14
(m, 2H, o-CHCF), 7.00-6.95 (m, 2H, o-CH), 6.91-6.82 (m, 4H, p-CH, m-CH), 4.35 (s, 2H, CHO). 13C NMR (376 MHz, CDCl3, 25 °C): δ = 163.9-161.4 (d, J = 246), 136.8 (d, J = 7.4), 129.7 (d,
J = 8.2), 122.6 (d, J = 2.9), 114.9 (d, J = 21.0), 114.0 (d, J = 23), 59.3 (d, J = 2.2). IR (CHCl3):
~ = 3071, 2984, 1589, 1446, 1221, 786, 690. HRMS (EI) m/z: calculated: 232.0700 ; measured:
232.0696.
Ligand Synthesis
Synthesis of the Onium Salts
1-(3-Formyl-2-hydroxy-5-pentylbenzyl)-4-methylpyridinium Bromide (11)
Pyridinium salt 11 was prepared according to GP1. The aldehyde (1.0 mmol, 0.30 g) was treated
with 4-methylpyridine (1.1 mmol, 0.11 g, 0.11 mL). The desired compound 11 (0.37 g, 92%) was
isolated as a light brown powder. [8]
C19H24BrNO2, MW: 377.1 g/mol. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 11.41 (s, 1H, Ar-OH),
9.86 (s, 1H, Ar-CHO), 9.40 (d, J = 6.7, 2H, o-Py-H), 8.39 (d, J = 2.0, 1H, Ar-H), 7.72 (d, J = 6.4,
2H, m-Py-H), 7.45 (d, J = 2.1, 1H, Ar-H), 6.24 (s, 2H, Ar-CH2-Py), 2.68–2.63 (m, 5H, Ar-CH2-
C4H9 and Py-CH3), 1.68–1.58 (m, 2H, (CH2)pentyl), 1.38–1.25 (m, 4H, (CH2)pentyl), 0.89 (t, J =
6.8, 3H, CH3).
The rest of the analytical data were in compliance to the literature known values.[8]
N-Benzyl-1-(5-(tert-butyl)-3-formyl-2-hydroxyphenyl)-N,N-dimethylmethylammonium Bromide (12)
Ammonium salt 12 was prepared according to GP1. The aldehyde (3.7 mmol, 1.00 g) was treated
with N,N-Dimethylbenzylamine (4.1 mmol, 0.55 g, 0.61 mL). The desired compound 12 (1.42 g,
95%) was isolated as a light brown powder.
C21H28BrNO2, MW: 405.13 g/mol. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 11.60 (s, 1H, Ar-
OH), 9.95 (s, 1H, Ar-CHO), 8.39 (d, J = 1.8, 1H, m-ArH), 7.74 (d, J = 1.8, 2H, ArH), 7.65 (d,
J = 7.0, 2H, ArH), 7.56-7.48 (m, 3H, ArH), 5.14 (s, 2H, CH2), 4.99 (s, 2H, CH2), 3.15 (s, 6H,
N(CH3)2), 1.39 (s, 9H, C(CH3)3).
The rest of the analytical data were in compliance to the literature known values.[9]
5-(tert-Butyl)-3-((diethylamino)methyl)-2-hydroxybenzaldehyde (13)[10]
The synthesis of 13 followed a literature known protocol.[10] Ethanol (15.0 mL) and 5-(tert-butyl)-
2-hydroxybenzaldehyde (1.0 equiv., 15.1 mmol, 2.69 g) were mixed and a solution of
formaldehyde in water (35%, 1.5 equiv., 22.7 mmol, 1.84 g, 1.84 mL) followed by diethylamine
(1.5 equiv., 22.7 mmol, 1.66 g, 2.37 mL) were added. The mixture was heated to reflux for 24 h.
The solvent was removed in vacuo and the residue diluted by DCM (20 mL). After drying over
MgSO4 and removal of the DCM the crude product was purified by column chromatography
(petrol ether/ethyl acetate 10:1, followed by the addition of 5% NEt3 to the eluent). The desired
pure aldehyde (2.19 g, 55%) was obtained as yellow oil.
C16H25NO2, MW: 263.19 g/mol. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 12.21 (bs, 1H, Ar-OH),
10.42 (s, 1H, CHO), 7.65 (d, J = 2.5,1H, m-ArH), 7.25 (d, J = 2.5, 1H, m-ArH), 3.81 (s, 2H, CH2),
2.65 (q, J = 7.2, 4H, NCH2), 1.28 (s, 9H, C(CH3)3), 1.13 (t, J = 7.2, 6H, NCH2CH3). 13C NMR (75
MHz, CDCl3, 25 °C): δ = 191.2, 160.5, 141.6, 132.2, 123.8, 123.5, 122.6, 56.6, 46.6, 34.2, 31.5,
11.3. IR (CHCl3): ~ = 2965, 2870, 1677, 1476, 1215, 962, 742, 611. HRMS (ESI) m/z:
calculated: 264.1958; measured: 264.1940.
N-(5-(tert-Butyl)-3-formyl-2-hydroxybenzyl)-N-diethyl-N-methylammonium Bromide (14)
In a dried Schlenk-flask trimethyloxoniumtetrafluoroborate (0.97 equiv., 1.94 mmol, 0.29 g) was
dissolved in dry DCM (25.0 mL) and cooled down 80 °C. At this temperature a solution of
aldehyde x (1.00 equiv., 2.00 mmol, 0.53 g) in DCM (5.0 mL) was added dropwise to the reaction
and the resulting solution stirred for 8 hours. The mixture was warmed up to ambient temperature
overnight and quenched by the addition of MeOH (1.0 mL). The resulting solution was stirred for
30 minutes at ambient temperature, and freed of the solvent in vacuo. The crude product was
diluted by DCM (5.0 mL) and carefully layered with n-hexanes (5.0 mL). After 12 h at -20 °C
fridge crystals were obtained. These were collected by filtration and dissolved in DCM (25.0 mL)
and lithium bromide (10 equiv., 19.4 mmol, 1.68 g) was added. Afterwards the mixture was stirred
for 2 h at ambient temperature. The precipitated salt was removed by filtration and the remaining
solvent under reduced pressure to yield the pure bromide salt 14 (0.61 g, 85%) as a white powder.
C17H28BrNO2, MW: 357.13 g/mol. M.p.: 173.1-178.5 °C 1H NMR (400 MHz, CDCl3, 25
°C): δ = 11.63 (s, 1H, Ar-OH), 9.93 (s, 1H, CHO), 8.50 (d, J = 2.4, m-ArH), 7.70 (d, J = 2.4, m-
ArH), 4.99 (s, 2H, NCH2Ar), 3.75-3.45 (m, J = 7.1, 4H, N(CH2CH3)2), 3.19 (s, 3H, NCH3), 1.49-
1.42 (t, J = 7.3, 6H, N(CH2CH3)2), 1.38 (s, 9H, C(CH3)3). 13C NMR (75 MHz, CDCl3, 25 °C): δ =
196.9, 158.7, 144.4, 141.6, 133.0, 120.4, 115.6, 58.5, 55.9, 31.4, 8.5. IR (CHCl3): ~ = 3421, 2959,
1649, 1476, 1061, 723. HRMS (ESI) m/z: calculated: 278.2115; measured: 278.2110.
(R,R)-(−)-N,N'-Bis(3-pentyl-5-(pyridinium-1-ylmethyl)salicylidene)-1,2-cyclohexanediamine dibromide (15)[8]
Ligand 15 was prepared according to GP2 with aldehyde 11 (2.0 equiv., 0.9 mmol, 328.0 mg) and
(1R,2R)-1,2-diaminocyclohexane (1.0 equiv., 0.45 mmol, 51.4 mg as a dark yellow powder
(329.3 mg, 91%).[8]
C42H54Br2N4O2, MW: 804.26 g/mol. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 14.13 (b, 2H, Ar-
OH), 9.44 (d, J = 9.7, 4H, o-Py-H), 8.41 (tt, J = 7.9, 1.4, 2H, p-Py-H), 8.32 (s, 2H, Ar-CH=N-Cy),
7.94 (t, J = 7.2, 4H, m-Py-H), 7.81 (d, J = 2.2, 2H, Ar-H), 7.13 (d, J = 1.9, 2H, Ar-H), 6.09 (m, 4H,
Ar-CH2-Py), 3.41 (m, 2H, Cy-HN=CHR)), 2.51 (m, 4H, Ar-CH2-C4H9), 1.98–1.85 (m, 4H, Cy-H2),
1.72–1.43 (m, 10H, Cy-H2 und (CH2)pentyl), 1.33–1.25 (m, 8H, (CH2)pentyl), 0.86 (t, J = 6.7, 6H,
(CH3)pentyl).
The rest of the analytical data were in compliance to the literature known values. [8]
(R,R)-(+)-N,N’-Bis(3-tert-butyl-5-((N-benzyl-N,N-dimethylammonium)- 1-ylmethyl)-salicylidene)-1,2-cyclohexadiamine dibromide (16)[9]
Ligand 16 was prepared according to GP2 with aldehyde 12 (2.0 equiv., 0.84 mmol, 341.6 mg) and
(1R,2R)-1,2-diaminocyclohexane (1.0 equiv., 0.42 mmol, 48.0 mg) as a yellow powder (345.6 mg,
92%).
C42H54Br2N4O2, MW: 888.36 g/mol. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 14.04 (bs, 2H, Ar-
OH), 8.37 (s, 2H, Ar-CH=N), 7.87 (s, 2H, Ar-H), 7.66 (m, 4H, Ar-H), 7.48-7.37 (m, 6H, Ar-H),
7.31 (bs, 2H, Ar-H), 5.10-4.95 (m, 6H, ArCH2), 4.86 (m, 2H, ArCH2), 3.41 (m, 2H, Cy-CH), 3.11
(s, 6H, NCH3), 3.07 (s, 6H, NCH3), 1.99-1.84 (m, 4H, Cy-CH2), 1.51-1.38 (m, 4H, cy-CH2), .123
(s, 18H, C(CH3)3).
The rest of the analytical data were in compliance to the literature known values.[9]
N-Benzyl-1-(3-((E)-(((1R,2R)-2-(((E)-3,5-di-tert-butyl-2-hydroxybenzyliden)amino)Cy)imino)methyl)-2-hydroxy-5-tert-butyl-benzyl)-N,N-dimethylammonium bromide (17)
Ligand 17 was prepared according to GP3 using HCl (1.0 equiv., 1.43 mmol, 0.71 mL 2M in
Et2O), to protonate (1R,2R)-1,2-diaminocyclohexane (1.0 equiv., 1.43 mmol, 0.16 g) in Et2O
(10.0 mL). For the condensation the hydrochloride 9b (1.0equiv., 0.98 mmol, 0.15 g) was dissolved
in 10.0 mL of MeOH and 3,5-Di-tert-butyl-2-hydroxybenzaldehyde (1.1 equiv., 1.08 mmol,
0.25 g), ammonium bromide 12 (1.0 equiv., 0.98 mmol, 0.25 g) and triethylamine (2.0 equiv.,
1.96 mmol, 0.20 g, 0.27 mL) were added subsequently (each one dissloved in 3.00 mL of MeOH).
The desired ligand 17 (0.85 mmol, 0.61 g, 85%) was obtained as a bright yellow solid.
C42H60BrN3O2, MW: 717.39 g/mol. M.p.: 218.2-220.7 °C decomposition. [α]20D (c = 0.10
mg/mL, DCM): +198.0. 1H NMR (500 MHz, CDCl3, 24 °C): δ = 14.21 (s, 1H, Ar-OH), 13.55 (s,
1H, Ar-OH), 8.29 (s, 1H, Ar-CH-N), 8.21 (s, 1H, Ar-CH-N), 7.75 (d, J = 2.60, 1H, Ar-H), 7.60 (d,
J = 7.66, 2H, Ar-H), 7.45-7.33(m, 3H, Ar-H), 7.27 (d, J = 2.69, 1H, Ar-H), 7.22 (d, J = 2.39, 1H,
Ar-H), 6.91 (d, J = 2.60, 1H, Ar-H), 5.03-4.71 (m, 4H, N-CH2-Ar), 3.03 (s, 6H, N-CH3), 1.89-1.49
(m, 8H, Cy-H2), 1.33 (s, 9H, tBuH), 1.19 (s, 9H, tBu-H), 1.17 (s, 9H, tBuH). 13C NMR (75 MHz,
CDCl3, 25 °C): δ =165.7, 164.8, 159.8, 158.0, 141.8, 140.2,136.7, 136.1 ,133.4, 131.2, 130.7,
129.2, 127.6, 127.1, 125.8, 118.3, 117.8, 114.8, 72.4, 71.5, 68.2,62.7, 49.1, 48.9, 35.0, 34.1, 34.1,
33.5, 32.7, 31.5, 31.4, 31.3, 31.0, 29.4, 29.4, 24.3, 24.2. IR (solid):~ = 3399, 2954, 2863, 2181,
1629, 1476, 1477, 1441, 1362, 923, 861, 730. HRMS (ESI) m/z: calculated 638.4680; measured:
638.4689.
N-(5-(tert-Butyl)-3-((E)-(((1R,2R)-2-(((E)-3,5-di-tert-butyl-2-hydroxybenzylidene)amino)methyl)-2-hydroxybenzyl)-N-diethyl-N-methylammonium Bromide (18)
Ligand 18 was prepared according to GP3 using HCl (1.0 equiv., 0.33 mmol, 82.4 µL, 4M in 1,4-
dioxane), to protonate (1R,2R)-1,2-diaminocyclohexane (1.0 equiv., 0.33 mmol, 38.4 mg) in Et2O
(1.0 mL). For the condensation the hydrochloride 9b was dissolved in MeOH (2.0 ml) and 3,5-di-
tert-butyl-2-hydroxybenzaldehyde (1.1 equiv., 0.36 mmol, 85.0 mg), ammonium bromide 14
(1.0 equiv., 0.33 mmol, 118.1 g) and triethylamine (2.0 equiv., 0.66 mmol, 66.7 mg, 91.4 µL) were
added subsequently (each one dissolved in 0.5 mL of MeOH). The desired ligand 18 (0.28 mmol,
190.0 mg, 86%) was obtained as a bright yellow solid.
C38H60BrN3O2, MW: 669.39 g/mol. M.p.: 155.1-165.1 °C decomposition. [α]20D (c = 0.18
mg/mL, DCM): +313.5. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 14.31 (s, 1H, ArOH), 13.60 (s,
1H, ArOH), 8.36 (s, 1H, CH=N), 8.29 (s, 1H, CH=N), 7.81 (d, J = 2.3, ArH), 7.35 (d, J = 2.4,
ArH), 7.28 (d, J = 2.3, ArH), 7.00 (d, J = 2.4, ArH), 4,85-4.57 (m, 2H, CH2N), 3.81-3.24 (m, 4H,
N(CH2CH3)2), 3.10 (s, 3H, NCH3), 2.03 (m, 1H, CyH), 1.91 (m, 3H, CyH), 1.72 (m, 2H, CyH), 1.49
(m, 2H, CyH), 1.39 (m, 15H, C(CH3)3, N(CH2CH3)3), 1.26 (m, 18H, C(CH3)3). 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 165.9, 164.9, 160.0, 158.1, 141.9, 140.4, 136.9, 136.1, 131.3, 127.2, 125.9,
118.4, 117.9, 114.7, 72.5, 71.7, 59.7, 56.0, 55.8, 35.2, 34.24, 34.20, 33.6, 32.8, 31.6, 31.4, 29.5,
24.46, 24.43, 8.5. IR (CHCl3):~ = 3411, 2954, 2864, 1630, 1477, 1036, 731. HRMS (ESI) m/z:
calculated: 590.4680; measured: 590.4699.
Catalysis
Isolation of Catalyst 3c
Catalyst 3c was formed as mentioned in GP3. To a solution of ligand 17 (1.0 equiv., 0.056 mmol,
40.1 mg) in DCM was given AlEt2Cl (1.1 equiv., 0.061 mmol, 7.4 mg, 61 µL, 1M in heptane). This
mixture was stirred for 48 h. To the solution was added dry n-pentane to percipitate the catalyst.
The percipitate was washed twice with dry n-pentane and dried under reduced pressure to yield the
desired catalyst as a yellow solid (33.1 mg, 76%).
C42H58AlBrClN3O2, MW: 779.28 g/mol. M.p.:>200 °C decomposition. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 8.44 (s, 1H, CHN), 8.32 (s, 1H, CHN), 8.12 (m, 1H, ArH), 7.69-7.42 (m, 7H,
ArH), 7.20 (d, J = 2.5, ArH), 5.30-5.20 (m, 1H, NCHPh), 5.18-5.06 (m, 1H, NCHPh), 5.05-4.85 (m,
2H, NCH2Ar), 3.64 (m, 2H, CyH), 3.14 (s, 3H, NCH3), 3.11 (s, 3H, NCH3), 2.55 (m, 2H, CyH),
2.10 (m, 2H, CyH), 1.59 (s, 9H, tBuH), 1.55-1.48 (m, 4H, CyH), 1.36 (s, 9H, tBuH), 1.33 (s, 9H,
tBuH). 13CNMR (75 MHz, CDCl3, 25 °C): δ = 165.9 (m), 162.2, 161.8, 140.2, 140.0, 139.5,
139.2, 133.8, 133.3, 131.1, 130.6, 129.2, 128.3, 127.9, 119.1, 118.6, 118.3, 67.6, 64.8, 63.8, 63.4,
48.9, 48.5, 35.5, 34.1, 34.0, 31.2, 31.1, 29.7, 27.8, 27.6, 24.0, 23.8. IR (CHCl3):~ = 2952, 2864,
1636, 1557, 1473, 1361, 1258, 865, 844, 705, 595. HRMS (ESI) m/z: calculated for [M]+
C42H58AlClN2O2: 698.4027; measured: 698.4009.
In situ formation of catalyst 3d
Catalyst 3d was formed as mentioned in GP3. To a solution of ligand x (1.0 equiv., 0.01 mmol,
6.7 mg) in DCM was added AlEt2Cl (1.0 equiv., 0.01 mmol, 1.0 mg, 10 µL, 1M in n-heptane). The
catalyst was used without further purification.
(1S,2S)-2-Bromo-1,2-diphenylethyl acetate (4a)
Acetate 4a was prepared according to GP4 using stilbenoxide (1.0 equiv., 0.2 mmol, 39.3 mg) and
isolated by column chromatography (petrol ether/ ethyl acetate 30:1) as a white solid (56.1 mg,
88%, er 92:8). The enantiomeric ratio was determined by HPLC: Chiralcel AD-H, n-hexane/ iPrOH
(99/1), 0.8 mL min-1, 210 nm, 14.8 min (major enantiomer) 16.4 min (minor enantiomer).
C16H15BrO2, MW: 319.20 g/mol. M.p.: 65.0 °C. [α]20D (c = 0.21 mg/mL, DCM): +107.1. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.24-7.15 (m, 8H, ArH), 7.14-7.08 (m, 2H, ArH), 6.22 (d,
1H, CHBr), 5.17 (d, J = 9.4, 1H, CHO), 2.17 (s, 3H, CH3-CO). 13C NMR (75 MHz, CDCl3, 21
°C): δ = 168.8, 137.8, 136.8, 128.8, 128.7, 128.62, 128.59, 128.4, 127.5, 78.7, 56.8, 21.3. IR
(CHCl3): ~ = 3056, 3031, 2969, 1742, 1369, 1223, 1021, 758, 697, 611, 537. HRMS (ESI) m/z:
calculated for [M+Na]+ C16H15BrO2Na: 343.0129; measured: 343.0122.
(1S,2S)-2-Bromo-1,2-di-p-tolylethyl acetate (4b)
Acetate 4b was prepared according to GP4 using 2,3-di-p-tolyloxirane ( 1.0 equiv. 0.2 mmol,
44.9 mg) and isolated by column chromatography (petrol ether/ ethyl acetate 30:1) as a colorless oil
(61.2 mg, 88%, er 91:9). The enantiomeric ratio was determined by HPLC: Chiralcel ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 10.35 min (major enantiomer) 14.35 min (minor
enantiomer).
C18H19BrO2, MW: 347.25 g/mol. [α]20D (c = 0.16 g/100mL, DCM): +98.9. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.14-7.09 (m, 2H, ArH), 7.05-6.96 (m, 6H, ArH), 6.21 (d, J = 9.5, 1H, CHBr),
5.18 (d, J = 9.3, 1H, CHO), 2.26 (s, 3H, ArCH3), 2.24 (s, 3H, ArCH3), 2.14 (s, 3H, CH3-CO). 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 169.8, 138.6, 138.4, 135.1, 133.9, 129.3, 129.1, 128.5, 127.5,
78.4, 57.0, 21.3. IR (CHCl3): ~ = 3027, 2922, 1741, 1370, 1224, 1019, 814, 727, 523. HRMS (EI)
m/z: Calculated for [M]+ C18H19BrO2: 346.0568; found: 346.0568.
(1S,2S)-2-Bromo-1,2-di-m-tolylethyl acetate (4c)
Acetate 4c was prepared according to GP4 using 2,3-di-m-tolyloxirane ( 1.0 equiv. 0.2 mmol,
44.9 mg) and isolated by coloumn chromatography (petrol ether/ ethyl acetate 30:1) as a colorless
oil, (59.1 mg, 85%, er 91:9). The enantiomeric ratio was determined by HPLC: Chiralcel ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm 10.67 min (major enantiomer) 15.36 min (minor
enantiomer).
C18H19BrO2, MW: 347.25 g/mol. [α]20D (c = 0.18 g/100 mL, DCM): +101.7. 1H NMR (400
MHz, CDCl3, 25 °C): δ = 7.08-6.87 (m, 8H, ArH), 6.18 (d, J = 9.3, 1H, CHBr), 5.12 (d, J = 9.3,
1H, CHO), 2.23 (s, 3H, ArCH3), 2.20 (s, 3H, ArCH3), 2.13 (s, 3H, CH3-CO). 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 169.8, 138.2, 138.0, 137.8, 136.8, 129.5, 129.31, 129.29, 128.4, 128.19,
128.17, 125.7, 124.6, 78.5, 57.1, 21.42, 21.37, 21.26. IR (CHCl3): ~ = 3024, 2921, 1742, 1370,
1222, 1024, 787, 710, 463.HRMS (EI) m/z: Calculated for [M]+ C18H19BrO2: 346.0568; measured:
346.0571.
(1S,2S)-2-Bromo-1,2-bis(4-fluorophenyl)ethyl acetate (4d)
Acetate 4d was prepared according to GP4 using 2,3-bis(4-fluorophenyl)oxirane ( 1.0 equiv.
0.2 mmol, 46.5 mg) and isolated by column chromatography (petrol ether/ ethyl acetate 30:1)as a
colorless oil (63.2 mg, 91%, er 95:5). The enantiomeric ratio was determined by HPLC: Chiralcel
ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 13.92 min (major enantiomer) 19.04 min
(minor enantiomer).
C16H13BrF2O2, MW: 355.18 g/mol. [α]20D (c = 0.24 g/100mL, DCM): +114.9. 1H NMR (400
MHz, CDCl3, 25 °C): δ = 7.24-7.17 (m, 2H, ArH), 7.15-7.07 (m, 2H, ArH), 6.97-6.87 (m, 4H,
ArH), 6.19 (d, J = 9.3, 1H, CHBr), 5.15 (d, J = 9.3, 1H, CHO), 2.19 (s, 3H, CH3-CO). 19F NMR
(376 MHz, CDCl3, 25 °C): δ = 112.1 to 112.2 (m), 112.4 to 112.6 (m). 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 169.5, 163.8 (d, J = 9.0), 161.3 (d, J = 9.4), 133.4 (d, J = 3.7), 132.4 (d,
J = 3.1), 130.3 (d, J = 8.7), 129.1 (d, J = 8.1), 115.7, 115.52, 115.46, 115.3, 77.9, 55.3, 21.0. IR
(CHCl3): ~ = 3075, 1741, 1605, 1509, 1218, 1159, 1028, 834, 735, 529. HRMS (EI) m/z:
Calculated for [M]+ C16H13BrF2O2: 354.0067; measured: 354.0066.
(1S,2S)-2-Bromo-1,2-bis(3-fluorophenyl)ethyl acetate (4e)
Acetate 4e was prepared according to GP4 using 2,3-bis(3-fluorophenyl)oxirane ( 1.0 equiv.
0.2 mmol, 46.5 mg) and isolated by coloumn chromatography (petrol ether/ ethyl acetate 30:1) as a
colurless oil (65.3 mg, 92%, er 96:4). The enantiomeric ratio was determined by HPLC: Chiralcel
ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 14.03 min (major enantiomer) 19.84 min
(minor enantiomer).
C16H13BrF2O2, MW: 355.18 g/mol. [α]20D (c = 0.15 g/100mL, DCM): +106.2. 1H NMR (500
MHz, CDCl3, 24 °C): δ = 7.25-7.15 (m, 2H, ArH), 7.06-6.98 (m, 2H, ArH), 6.97-6.88 (m, 4H,
ArH), 6.18 (d, J = 8.9, 1H, CHBr), 5.12 (d, J = 9.0, 1H, CHO), 2.20 (s, 3H, CH3-CO). 19F NMR
(376 MHz, CDCl3, 25 °C): δ = 112.01 to 112.07 (m), 112.11 to 112.2 (m). 13C NMR (75
MHz, CDCl3, 25 °C): δ = 170.0, 163.8 (d, J = 9.8), 161.4 (d, J = 9.5), 139.9 (d, J = 7.3), 130.2 (d,
J = 8.6), 130.0 (d, J = 8.0), 124.3 (d, J = 3.3), 123.3 (d, J = 3.0), 116.0 (d, J = 20.7), 115.93 (d,
J = 5.9), 115.88 (d, J = 2.0), 115.7 (d, J = 7.4), 114.3 (d, J = 22.7), 77.7, 55.0, 21.1. IR (CHCl3):
~ = 3065, 1746, 1593, 1449, 1223, 906, 727, 715, 481. HRMS (ESI) m/z: Calculated for [M]+
C16H13BrF2O2: 354.0067; measured: 354.0061.
(1S,2S)-2-Bromo-1,2-bis(4-(trifluoromethyl)phenyl)ethyl acetate (4f)
Acetate 4f was prepared according to GP4 using 2,3-bis(4-(trifluoromethyl)phenyl)oxirane
( 1.0 equiv. 0.2 mmol, 66.5 mg) and isolated by coloumn chromatography (petrol ether/ ethyl
acetate 30:1) as a colorless oil (81.0 mg, 89%, er 95.5:4.5,). The enantiomeric ratio was determined
by HPLC: Chiralcel ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 14.40 min (major
enantiomer) 18.24 min (minor enantiomer).
C18H13BrF6O2, MW: 455.19 g/mol. [α]20D (c = 0.35 g/100mL, DCM): +76.6. 1H NMR (400
MHz, CDCl3, 25 °C): δ = 7.51-7.41 (m, 4H, ArH), 7.37-7.29 (m, 2H, ArH), 7.27-7.19 (m, 2H,
ArH), 6.21 (d, J = 8.6, 1H, CHBr), 5.16 (d, J = 8.6, 1H, CHO), 2.15 (s, 3H, CH3-CO). 19F NMR
(376 MHz, CDCl3, 25 °C): δ = -62.83, -62.84. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 169.5,
141.2, 140.2, 131.3 (d, J = 5.1), 131.0 (d, J = 5.1), 129.1, 127.9, 125.8 (m), 125.6 (m), 125.1 (d,
J = 8.8), 122.4 (d, J = 8.6), 77.5, 54.4, 21.1. IR (CHCl3):~ = 3077, 2961, 1747, 1322, 1223, 1165,
1111, 1067, 1018, 846, 607. HRMS (EI) m/z: Calculated for [M-F]+ C18H13BrF5: 435.0019;
measured: 435.0023.
(1S,2S)-2-Bromo-1,2-bis(3-(trifluoromethyl)phenyl)ethyl acetate (4g)
Acetate 4g was prepared according to GP4 using 2,3-bis(3-(trifluoromethyl)phenyl)oxirane
( 1.0 equiv. 0.2 mmol, 66.5 mg) and isolated by coloumn chromatography (petrol ether/ ethyl
acetate 30:1) as a colorless oil (74.6 mg, 82%, er 88:12). The enantiomeric ratio was determined by
HPLC: Chiralcel ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 14.08 min (minor
enantiomer) 15.52 min (major enantiomer).
C18H13BrF6O2, MW: 455.19 g/mol. [α]20D (c = 0.15 g/100 mL, DCM): +71.8. 1H NMR (400
MHz, CDCl3, 25 °C): δ = 7.56-7.48 (m, 2H, ArH), 7.47-7.28 (m, 6H, ArH), 6.24 (d, J = 8.2, 1H,
CHBr), 5.19 (d, J = 8.2, 1H, CHO), 2.21 (s, 3H, CH3-CO). 19F NMR (376 MHz, CDCl3, 25
°C): δ = -62.95, -62.98. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 169.4, 138.1, 137.2, 131.8,
131.5-130.4 (m), 130.7, 129.2, 128.9, 125.8-125.4 (m), 124.9 (d, J = 9.3), 124.1-123.9 (m), 122.2
(d, J = 9.3), 77.6, 54.4, 20.5. IR (CHCl3):~ = 3069, 2961, 1747, 1326, 1222, 1163, 1119, 1073,
1033, 806, 699, 662. HRMS (EI) m/z: Calculated for [M-F]+: 435.0019; measured: 435.0019.
(1S,2S)-2-Bromo-1,2-bis(3-chlorophenyl)ethyl acetate (4h)
Br
OO
4h
Cl
Cl
Acetate 4h was prepared according to GP4 using 2,3-bis(3-chlorophenyl)oxirane ( 1.0 equiv.
0.2 mmol, 53.0 mg) and isolated by coloumn chromatography (petrol ether/ ethyl acetate 30:1) as a
colorless oil (69.1 mg, 89%, er 90.5:9.5). The enantiomeric ratio was determined by HPLC:
Chiralcel ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 14.30 min (major enantiomer)
18.16 min (minor enantiomer).
C16H13BrCl2O2, MW: 388.08 g/mol. [α]20D (c = 0.17 g/100 mL, DCM): +61.9. 1H NMR (400
MHz, CDCl3, 25 °C): δ = 7.25-7.02 (m, 7H, ArH), 6.96-6.91 (m, 1H, ArH), 6.10 (d, J = 8.8, 1H,
CHBr), 5.03 (d, J = 8.8, 1H, CHO), 2.14 (s, 3H, CH3-CO). 13C NMR (75 MHz, CDCl3, 25
°C): δ = 169.5, 139.4, 138.5, 134.53, 134.51, 129.9, 129.7, 129.1, 129.0, 128.9, 127.4, 126.8,
125.8, 77.6, 54.9, 21.1. IR (CHCl3):~ = 3064, 1744, 1575, 1430, 1371, 1219, 1028, 882, 787, 732,
693, 671, 465. HRMS (EI) m/z: Calculated for [M]+ C16H13BrCl2O2: 385.9476; measured:
385.9489.
(1S,2S)-2-Bromo-1,2-bis(3-methoxyphenyl)ethyl acetate (4i)
Acetate 4i was prepared according to GP4 using 2,3-bis(3-methoxyphenyl)oxirane ( 1.0 equiv.
0.2 mmol, 44.9 mg) and isolated by coloumn chromatography (petrol ether/ ethyl acetate 10:1) as a
colorless oil (64.5 mg, 85%, er 91:9). The enantiomeric ratio was determined by HPLC: Chiralcel
ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm, 25.87 min (major enantiomer) 39.52 min
(minor enantiomer).
C18H19BrO4, MW: 379.25 g/mol. [α]20D (c = 0.15 g/100 mL, DCM): +76.6. 1H NMR (500 MHz,
CDCl3, 24 °C): δ = 7.16-7.06 (m, 2H, ArH), 6.87-6.64 (m, 6H, ArH), 6.23 (d, J = 9.5, 1H, CHBr),
5.15 (d, J = 9.3, 1H, CHO), 3.73 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 2.18 (s, 3H, CH3-CO). 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 169.9, 159.6, 159.4, 139.2, 138.3, 129.6, 129.4, 121.0, 119.8,
114.5, 114.2, 113.1, 78.4, 56.7, 55.4, 55.3, 21.2. IR (CHCl3):~ = 3002, 2960, 2835, 1743, 1600,
1586, 1491, 1455, 1435, 1371, 1261, 1219, 1152, 1027, 873, 785, 712, 698, 487. HRMS (EI) m/z:
Calculated for [M]+ C18H19BrO4: 378.0467; found: 378.0462.
Derivatization
(1S,2R)-2-Azido-1,2-diphenylethyl acetate (6)
The synthesis of 6 was inspired by a literature known procedure.[11] The protected bromohydrin x
(1.0 equiv., 0.25 mmol, 80.4 mg; 91:9 er) was dissolved in dry DMF (0.35 mL) and sodium azide
(1.5 equiv., 0.38 mmol, 24.6 mg) was added. The mixture was heated to 85 °C and stirred at that
temperature for 36 h. The reaction was quenched by the addition of water (2.00 mL) and extracted
three times with Et2O (10.00 mL). The combined organic phases were washed with brine (20 mL)
three times, dried over MgSO4 and the solvent was removed under reduced pressure. After workup
the desired compound was obtained as a colorless oil (64.0 mg, 90%, 87:13 er). The enantiomeric
ratio was determined by HPLC: Chiralcel ODH, nhexane/iPrOH (99/1), 0.8 mL min-1, 210 nm,
15.25 min (major enantiomer) 18.24 min (minor enantiomer).
C16H15N3O2, MW: 281.32 g/mol. [α]20D (c = 0.18 g/100 mL, DCM): +36.6. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.35-7.29 (m, 6H, ArH), 7.26-7.18 (m, 4H, ArH), 5.95 (d, J = 6.5, 1H, CHN),
4.90 (d, J = 6.5, 1H, CHO), 2.00 (s, 3H, CH3CO). 13C NMR (75 MHz, CDCl3, 25 °C): δ = 169.5,
136.2, 135.7, 128.76, 128.74, 128.6, 128.3, 127.91, 127.86, 77.6, 69.1, 21.0. IR (CHCl3):~ = 3065,
2101, 1744, 1371, 1222, 1026, 761, 699. HRMS (EI) m/z: Calculated for [M-C7H6BrN3]+ C9H9O2:
149.0603; measured: 149.0606.
(1S,2R)-2-Azido-1,2-diphenylethylethan-1-ol (7)
Azido acetate 6 (1.0 equiv., 0.06 mmol, 16.9 mg) was dissolved in a mixture of water and methanol
(1:4, 0.30 mL), potassium carbonate (2.0 equiv., 0.12 mmol, 16.6 mg) was added and the resulting
mixture was stirred for one hour at ambient temperature. The mixture was extracted three times
with diethyl ether (2.0 mL). The combined organic phases were dried over sodium sulfate and the
solvent was removed under reduced pressure. Column chromatography of the crude product
yielded the desired azido alcohol (15.4 mg, 91%) as colorless oil.
C14H13N3O, MW: 239.28 g/mol. [α]20D (c = 0.13 g/100 mL, DCM): 61.2. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.37-7.27 (m, 6H, ArH), 7.26-7.20 (m, 4H, ArH), 4.80 (d, J = 6.6, 1H, CHN),
4.66 (d, J = 6.6, 1H, CHO), 2.09 (bs, 1H, OH).
The rest of the analytical data were in compliance to the literature known values. [11]
(1S,2R)-1,2-Diphenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl acetate (8)
The synthesis of molecule 8 was in analogy to a literature known method.[12,13] Azido acetate 6
(1.00 equiv., 0.100 mmol, 28.1 mg), copper (II) acetate (0.10 equiv., 0.010 mmol, 2.0 mg) and 2-
aminophenol (0.05 equiv., 0.005 mmol, 0.5 mg) were dissolved in DCM (0.2 mL) and mixed with
water (0.2 mL). Phenyl acetylene (1.00 equiv., 0.100 mmol, 10.2 mg, 9.5 µL) was added dropwise
and the mixture was stirred for 12 hours at ambient temperature. Afterwards the reaction was
extracted three times with DCM (2.0 mL) and the combined organic phases were washed with
brine (3.0 mL) and dried over sodium sulfate. After removal of the solvent under reduced pressure,
the crude product was purified by column chromatography (petrol ether/ethyl acetate 5:1) to yield
the desired product 7 as a white solid (29.9 mg, 89%).
C24H21N3O2, MW: 383.45 g/mol. M.p.: 135.1-138.5 °C. [α]20D (c = 0.13 g/100 mL, DCM):
15.3. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.69(d, J = 7.5, 2H, ArH), 7.56 (m, 2H, ArH), 7.55
(s, 1H, CHN3), 7.41-7.33 (m, 5H, ArH), 7.31-7.28 (m, 3H, ArH), 6.83 (d, J = 9.1, 1H, CHN(CN)),
5.86 (d, J = 9.0, 1H, CHO), 1.92 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3, 25 °C): δ = 169.2,
147.5, 136.6, 135.4, 130.5, 129.3, 129.04, 128.97, 128.89, 128.7, 128.5, 128.3, 127.2, 125.8, 119.8,
75.5, 69.2, 20.9. IR (CHCl3):~ = 3125, 3083, 3033, 1737, 1370, 1301, 1025, 766, 698, 560.
HRMS (ESI) m/z: Calculated for [M+Na]+ C24H21N3O2: 406.1526; measured: 406.1517.
Kinetic Comparison between catalysts 3d and 3e
-5
5
15
25
35
45
55
65
0 5 10 15 20 25 30
Yield (%)
Time (h)
catalyst 3d
catalyst 3e
Spectral data
cis-2,3-Bis(fluorophenyl)oxirane (1b)
5-(tert-Butyl)-3-((diethylamino)methyl)-2-hydroxybenzaldehyde (13)
N-(5-(tert-Butyl)-3-formyl-2-hydroxybenzyl)-N-diethyl-N-methylammonium Bromide (14)
N-Benzyl-1-(3-((E)-(((1R,2R)-2-(((E)-3,5-di-tert-butyl-2-hydroxybenzyliden)amino)Cy)imino)methyl)-2-hydroxy-5-tert-butyl-benzyl)-N,N-dimethylammonium bromide (17)
N-(5-(tert-Butyl)-3-((E)-(((1R,2R)-2-(((E)-3,5-di-tert-butyl-2-hydroxybenzylidene)amino)methyl)-2-hydroxybenzyl)-N-diethyl-N-methylammonium Bromide (18)
Catalyst 3c
(1S,2S)-2-Bromo-1,2-diphenylethyl acetate (4a)
(1S,2S)-2-Bromo-
1,2-di-p-tolylethyl acetate (4b)
(1S,2S)-2-
Bromo-1,2-di-m-tolylethyl acetate (4c)
(1S,2S)-2-Bromo-1,2-bis(4-fluorophenyl)ethyl acetate (4d)
(1S,2S)-2-Bromo-1,2-bis(3-fluorophenyl)ethyl acetate (4e)
(1S,2S)-2-Bromo-1,2-bis(4-(trifluoromethyl)phenyl)ethyl acetate (4f)
(1S,2S)-2-Bromo-1,2-bis(3-(trifluoromethyl)phenyl)ethyl acetate (4g)
(1S,2S)-2-Bromo-1,2-bis(3-chlorophenyl)ethyl acetate (4h)
(1S,2S)-2-Bromo-1,2-bis(3-methoxyphenyl)ethyl acetate (4i)
(1S,2R)-2-Azido-1,2-diphenylethyl acetate (6)
(1S,2R)-1,2-Diphenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethyl acetate (8)
HPLC-Data
References
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